I. Field of the Invention
This invention relates generally to a method of modulating the proliferation of microorganisms or other infectious vectors and, more particularly, to a method of introducing a neurochemical to augment, repress or otherwise affect the growth of Gram-reactive organisms. The process involves the introduction (or application) of effective amounts of a group of neurochemicals known as the catecholamines. Each microorganism tested has been shown to have specific requirements for one or more of the subject catecholamines. Depending on the catecholamine being employed, suppression or enhancement of growth may be effected. Furthermore, growth regulation can be effected in vivo and/or in vitro. The characterization of the receptor through which the catecholamine binds to the cell or cellular components as novel, enables further control of cell growth by the application of either receptor agonists or antagonists specific for this novel receptor.
II. Discussion of the Prior Art
Sepsis is the generally febrile pathologic state resulting from the presence of microorganisms or their poisonous products in the blood stream particularly in humans or other mammals. It occurs when spreading infectious agents are not successfully arrested within the lymph nodes, and thus directly invade venous channels. Although it is not uncommon to have periodic invasions of bacteria into the blood stream, called bacteremia, these outbursts are normally handled quickly and effectively by macrophages circulating in the blood. However, in some circumstances, such large numbers of bacteria may be involved in the invasion that the macrophages are overwhelmed and under-effective, resulting in the symptoms of fever, chills, general malaise and lethargy known as septicemia. In aggravated cases, it is possible that organisms reach such a high population within the circulation that they circulate in clumps. Under these conditions, it is possible that these circulating clumps may lodge within organs and produce large numbers of microabscesses, a situation which is called septicoyemia.
Traditional treatment of sepsis, septicemia, or septicoyemia is performed using antimicrobial agents, typically in conjunction with the use of vasoactive drugs such as norepinephrine and dopamine. These antimicrobial agents are typically designed to affect bacterial wall structure or bacterial metabolic processes. Such agents may be particularly targeted at a specific metabolic process or cellular receptor. However, despite this specificity, conventional antimicrobial therapy is unsuccessful in a large number of cases. In particular, it has been documented that up to 60% of all patients diagnosed with sepsis eventually succumb to the condition. Thus, despite the great strides forward, there remains great need for more specific and more effective antimicrobial agents or treatment protocols.
The primary role for the use of vasoactive drugs in septic conditions has been the restoration of normal hemodynamics. A typical clinical picture involving sepsis is the patient who fails to respond to traditional treatment or who undergoes intensive antibiotic therapy and apparent resolution of sepsis, with improvement in condition two to three days post admission to hospital. However, nearly 40% of patients relapse on the third to fourth day of treatment, with death ensuing rapidly thereafter. My recent data indicates that the use of catecholamines (such as norepinephrine and dopamine) as the preferred vasoactive agents may, in fact, be an essential factor contributing to the worsening clinical condition. My data indicates that administration of catecholamines to patients in these conditions results in providing some bacteria with a potent growth stimulus that permits rapid proliferation bacteria and eventual death of the patient, even in the face of appropriate antibiotic therapy.
Catecholamines in humans are a class of hormones that evoke a response by activation of adenyl cyclase. These compounds are targeted to specific hormone receptors in mammals and produce varied responses, depending upon the nature of the target tissue. The majority of catecholamines evoke their characteristic response by influencing the activity of pre-existing cellular enzyme systems. Thus, the response evoked may be almost instantaneous, such as in the case of neurotransmitters including norepinephrine and epinephrine. Norepinephrine, epinephrine and dopamine are the characteristic hormones of the mammalian sympathetic nervous system. All are amine derivatives of the catechol nucleus (dihydroxybenzene). These compounds have clearly identified peripheral effects. Classic feedback inhibition processes control the production of these compounds, in which the rate limiting step in the pathway is hydroxylation of the amino acid precursor tyrosine to form dihydroxyphenylalanine (dopa). In mammals, synthesis of catecholamines is a unique feature of sympathetic nervous tissue. However, in certain disease states, hormone producing tumors may release catecholamines directly into the circulation and, thus, manifest peripheral effects of these compounds as a result of plasma concentration instead of local tissue concentration. Other states, such as stress, are also classic activators of the production of catecholamines concomitant with the presumed suppression of the immune system. Otherwise, most manifest a non-circulatory effect.
Jones, et al., among others, have noted a severalfold increase in plasma norepinephrine and epinephrine levels during bacteremia. This increase has been attributed to activation of the adrenal medulla and peripheral sympathetic fibers. They suggest that plasma catecholamines may be an indicator of lethality, since in all reported instances, the mean values for plasma norepinephrine and epinephrine were higher in nonsurviving rats. The purpose of their study was to quantitate the levels of peripheral sympathetic activation as indicated by plasma catecholamine levels during sepsis. The actual reason for the increase was not the primary focus and possible blockage of re-uptake at neuronal sites was not addressed.
Although bacteria lack a nervous system and, thus, have no apparent need for neurotransmitters such as norepinephrine, epinephrine and dopamine, I have recently discovered that the presence of these chemicals in their environment may positively or negatively influence the growth of Gram-negative or Gram-positive bacteria. Based upon this discovery, I have devised a method of treatment of the pathologic state of a patient in order to modulate the growth of such infectious agents, as well as regulate viral, phage, plasmid, microorganism, or parasite reproduction.
Such a class-dependent response presents great opportunity for novel approaches in drug design. For example, the identification of the receptors by which bacteria may use these neurochemicals leads to the design of receptor antagonists which may be as potent in the control of bacterial growth as current antimicrobial therapy, including the application of antibiotics. Gram-negative bacteria having a growth-enhancing response to neurochemicals are open to treatment by any inhibitor which intercedes at any point in the catecholamine biosynthetic pathway, such as monoamine oxidase inhibitors, in order to interrupt specific steps in the conversion pathways of these catecholamines.
It is accordingly a principal object of the present invention to provide a new and improved method for the treatment of sepsis, septicemia or septicoyemia.
Another object of the present invention is to provide a new and improved method for the treatment of living patients suffering the effects of a microbial, parasitic or viral infection.
It is yet another object of the present invention to provide a new and improved method for enhancing or suppressing the proliferation of microbial or viral agents or vectors in a living system.
A further object of the present invention is to provide a new and improved method for the suppression of bacterial replication within living patients.
Another object of the present invention is to provide a new method for specifically binding the novel receptor identified herein.
Yet another object of the present invention is to provide a new method for application in the field of the design of drugs and therapeutics, by which recognition of this novel receptor identified herein is useful in suppressing the proliferation of infectious agents.